The overall goals of this grant are to use novel chemical scaffolds developed at Gliatech in conjunction with combinatorial chemistry techniques to generate unique and diverse imidazole-based libraries for subsequent biological testing. The libraries would provide entry in drug development for CNS, cardiovascular, inflammation, allergy, antifungal, antiviral, and anticancer indications. Specific Aims of this grant are to utilize recently developed chemistry that has provide two diverse scaffolds (a) 4-but-3-ynyl-l-(triphenylmethyl)imidazole and (b) 1-((3,3-dimethyl-3-silabutoxy)methyl)-2-(phenylsulfonyl)imidazole to generate (1) new 1H-4 (5)-substituted imidazole and (2) multi- substituted imidazole compound libraries of 100-200 compounds. Specific aim (3) would use high-throughput receptor ligand assays to screen these unique imidazole libraries and identify novel lead candidates for several G-protein linked receptors (i.e. H1, H2, H3, alpha1, alpha2, 5- HT3, 5-HT4, and I2). The research outlined in this grant will not only provide novel compound libraries for biological testing but will provide the foundation for future expanded combinatorial library construction. In addition, selected potential targets have been identified based on literature precedent and pilot biological data. The screening of these libraries would provide rapid identification of lead candidates for future drug development as well as allow for expanded biological screening into novel therapeutic areas. PROPOSED COMMERCIAL APPLICATION: Phase I chemistry studies target the development of imidazole-base libraries using recently developed diverse scaffolds and combinatorial techniques. These studies would provide for library construction, biological testing, and identification of novel therapeutics for several therapeutic areas.